Embryonic Dopamine Neurons for Severe Parkinson’s Disease
Embryonic Dopamine Neurons for Severe Parkinson’s Disease
Abstract & Commentary
Source: Freed CR, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344:710-719.
For more than 2 decades, transplants of human embryonic dopamine neurons have been performed in patients with Parkinson’s disease in an attempt to treat the symptoms or halt the progression of the disease. Although there are numerous reports of patients who have benefited from the procedure, these results must be interpreted with caution. Prior to the present study, there were no double-blind trials of fetal tissue transplantation in Parkinson’s disease, and the number of patients reported in open-label series was small. This study by Freed and colleagues generated tremendous interest in the scientific community and in the lay press. Such a careful, double-blind, controlled study of fetal tissue transplantation in Parkinson’s disease will not likely be repeated. It is, thus, worthwhile to consider this landmark report in some detail.
The study was performed as a collaborative effort between Columbia-Presbyterian Medical Center, the University of Colorado School of Medicine, and North Shore University Hospital. Patients were eligible to enroll if they had Parkinson’s disease of at least 7 years duration, with good response to levodopa and no evidence of dementia or hallucinations. They were evaluated before surgery and at 4-, 8-, and 12-month intervals after surgery. Evaluations included examinations in the on and off state using standard clinical rating scales for Parkinson’s disease and quantitative 18-flurodopa PET scanning (which measures the presynaptic nigrostriatal dopaminergic pathway). The primary outcome variable of the study was the change in patients’ perception of their global functioning, as measured by a quantitative scale.
Patients were randomly assigned to receive either placebo or active transplant. In the active group, 4 human embryonic mesencephalic extracts were implanted bilaterally into the putamen using a stereotactic approach through frontal burr holes. Two extracts were implanted per side, extending the full anterior-posterior dimension of the putamen. Physicians, nurses, and PET scanning technicians who cared for patients were unaware of their assignment to either active transplant or placebo. Only the statistician, safety monitoring board, and neurosurgeons in Colorado were aware of the assignment. Patients who underwent placebo surgery had burr holes drilled in the skull, but the dura was not pierced. On completion of the double-blind phase, all patients were offered the option of active transplant; 14 of 20 patients in the placebo arm underwent the procedure.
The study yielded many important results. Rigidity and bradykinesia, as measured by clinical rating scales, improved after transplantation. Patients younger than 60 years had modest improvements on global rating, whereas those older than 60 years did not improve. However, there was no statistically significant difference in the primary outcome variable between patients who received active transplants and those who received placebo surgery.
A total of 16 out of 19 patients who underwent active transplantation experienced statistically significant increases in 18-flurodopa uptake in the putamen, indicating that embryonic dopaminergic cells engrafted successfully. There was no difference in the extent of re-innervation of the putamen between older and younger patients. Two patients died during the study—1 in an automobile accident and 1 of a myocardial infarction. In the latter case, death occurred 3 years after transplantation. Examination of this patient’s brain showed dopamine-neuron outgrowth extending the entire length and breadth of the putamen. These data support the assertion that the transplant technique was sufficient to fully re-innervate the striatum in the majority of patients.
Nine serious adverse events occurred in the transplant group; most were judged unrelated to transplantation. More concerning, of 33 patients who ultimately received transplants, 5 developed involuntary dystonic and dyskinetic movements; these persisted despite reduction or even elimination of levodopa. In several patients, involuntary movements were severe enough to pose a significant risk to their ability to perform activities of daily living, including swallowing. Based on this information, 6 patients in the sham group who had yet to decide whether to undergo the active procedure were advised against it.
Commentary
Few neurologists escaped the news coverage announcing the results of the transplant study. The study generated considerable interest for several reasons. Many people raised ethical concerns over the use of a placebo surgical arm. In retrospect, this was critical to the power of the study, as 2 patients in the placebo arm reported substantial benefits at 1-year follow-up prior to unblinding. A full discussion of the political, ethical, and moral consequences of the use of fetal tissue is beyond the scope of this review.
Most lay reports summarizing this transplant study called it a resounding failure. This is an unfortunate distortion of the results. As proof of principle, this study showed that fetal dopaminergic cells successfully engraft into both older and younger patients, and that re-innervation of the striatum is probably complete by three years after transplant. Unfortunately, dopaminergic re-innervation of the striatum using this technique is not adequate to produce a clinically significant benefit in younger patients. The technique does not benefit patients older than 60 years at all. One explanation for this result is that neurodegenerative changes downstream from the nigrostriatal pathway contribute significantly to patients’ deficits in advanced Parkinson’s disease. In a sense, this is not a surprise, as these patients often have incomplete response to treatment with levodopa.
The most unexpected and concerning result of this study was the development of disabling dyskinesias in younger patients who were successfully engrafted. The fact that dyskinesias persisted after levodopa was eliminated proves that the engrafted cells generated them. For these patients, such "run-away dyskinesias" present a terrible problem, as they cannot be terminated by medication adjustments and they may be very resistant to treatment. Presumably, these dyskinesias result from inappropriate or aberrant re-innervation of the striatum. Until the mechanisms responsible for generating these involuntary movements are fully understood, it would be hard to recommend transplantation of any dopaminergic cell line in humans as a treatment for Parkinson’s disease. —Steven Frucht
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